After death, numerous degradation processes begin, in which the cells and organs of the body are destroyed. Researchers have now partially reversed these processes. To do this, they connected the pigs to a system one hour after they died, which, like a heart-lung machine, pumps a fluid through the body that transports oxygen and nutrients to the organs. This treatment ensured that cell breakdown was stopped and repair processes were set in motion. Within six hours, the treated animals’ hearts started beating again and their circulation got going. The findings could help extend the life of human donor organs, but also raise ethical questions about the definition of death.
When mammalian blood flow stops—whether temporarily due to a heart attack or permanently after cardiac arrest—the lack of oxygen and nutrients triggers a cascade of events leading to cell death and organ damage. If the blood flow is restored, the actually vital oxygen in the damaged cells causes further problems, so-called reperfusion damage. In the case of organ donation, the problem has so far been contained by quickly cooling down the removed organs, so that the harmful processes take place more slowly. So far, however, what happens after death has mostly been considered irreversible.
stop cell death
New research results from a team led by David Andrijevic from Yale University in Connecticut are now questioning previous assumptions: the researchers have developed a system called OrganEx, with which they were able to determine important cell and organ functions in pigs one hour after their cardiac arrest to restore. “Not all cells die immediately, but there is a longer sequence of events,” explains Andrijevic. “It’s a process that you can intervene in, stop, and restore some cellular function.”
OrganEx is similar to a heart-lung machine, also known as Extracorporeal Membrane Oxygenation, or ECMO for short. However, while this pumps the patient’s own blood through their body and enriches it with oxygen outside the body, OrganEx relies on an artificial liquid, a so-called cryoprotective perfusate. This fluid carries oxygen using a molecule called hemopure, a synthetic variant of the red blood pigment hemoglobin. In addition, it is enriched with various drugs that are intended to prevent reperfusion damage, inflammation and blood clots, among other things.
Pigs as test organisms
OrganEx is the evolution of a system called BrainEx, which the research team used to restore specific cellular functions to the brains of decapitated pigs back in 2019. “If we were able to restore certain cellular functions in the dead brain, an organ known to be the most vulnerable to insufficient blood supply, we hypothesized that something similar could be achieved in other vital transplantable organs as well,” says Andrijevic’s colleague Nenad Sestan.
For the practical test of OrganEx, the researchers stunned domestic pigs aged ten to twelve weeks and induced cardiac arrest in them. They then left the dead animals at room temperature for an hour before connecting the OrganEx system. For comparison, they used a conventional heart-lung machine in some animals instead. The animals were treated in this way for six hours. The researchers then examined the permeability of the blood vessels, the functionality of the organs and also analyzed at the cell level which genes were activated – an indication of the molecular processes taking place in the cell.
Organs functional even after hours
The result: After six hours of treatment with OrganEx, the organs of the deceased pigs were largely functional and many key cellular functions were restored. “Under the microscope, it was difficult to distinguish a healthy organ from an organ that had been treated with OrganEx technology after death,” reports Andrijevic’s colleague Zvonimir Vrselja. Even the heart regained its ability to contract. “We were, to our surprise, able to restore blood circulation throughout the body,” said Sestan. The researchers also found cell activity in some areas of the brains of the killed pigs – but no organized electrical activity that would indicate consciousness. When the researchers examined the treated animals, they even observed involuntary spontaneous muscle movements in the head and neck area, suggesting that even some motor functions were preserved.
“This system and the knowledge gained with it have great potential for a wide range of clinical applications,” comments Uta Dahmen, Head of Experimental Transplantation Surgery at Jena University Hospital, who was not involved in the study. “In transplantation medicine, use for ‘organ repair’, the improvement of previously damaged organs, before transplantation is conceivable. It can also be used in other situations after a temporary reduced blood flow to organs, such as after a heart attack. However, there is still a long way to go from a promising experimental study to routine clinical use of a new medical device.”
New ethical questions
At the same time, the potential new possibilities also raise new ethical questions: When is a patient really dead? Is it ethical to keep your organs functional for a transplant via OrganEx, but let the patient die himself? Commenting on the study, also published in the journal Nature, Brendan Parent, research director for transplant ethics and policy at New York University, writes that the medical and biological determination of death may need to be revised. “To be better prepared for this possibility, physicians may need to rethink the way they use perfusion systems,” said Parent.
Source: David Andrijevic (Yale School of Medicine, USA) et al., Nature, doi: 10.1038/s41586-022-05016-1